Pluripotent Transcription Factors Possess Distinct Roles in Normal versus Transformed Human Stem Cells
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{"title"=>"Pluripotent Transcription Factors Possess Distinct Roles in Normal versus Transformed Human Stem Cells", "type"=>"journal", "authors"=>[{"first_name"=>"Junfeng", "last_name"=>"Ji", "scopus_author_id"=>"55425832800"}, {"first_name"=>"Tamra E.", "last_name"=>"Werbowetski-Ogilvie", "scopus_author_id"=>"12446333000"}, {"first_name"=>"Bonan", "last_name"=>"Zhong", "scopus_author_id"=>"38762641500"}, {"first_name"=>"Seok Ho", "last_name"=>"Hong", "scopus_author_id"=>"34769814700"}, {"first_name"=>"Mickie", "last_name"=>"Bhatia", "scopus_author_id"=>"7201641055"}], "year"=>2009, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"77649275200", "pmid"=>"19956629", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pui"=>"368587329", "issn"=>"19326203", "scopus"=>"2-s2.0-77649275200", "doi"=>"10.1371/journal.pone.0008065"}, "id"=>"e927fa76-d0ff-33c3-a906-f60f10601960", "abstract"=>"BACKGROUND: Cancer and normal stem cells (SCs) share proliferative properties of self-renewal and expression of key transcription factors (TFs). Despite similar TF identities, the functional role of specific TFs responsible for retaining SC state has yet to be examined in cancer. METHODOLOGY/PRINCIPAL FINDINGS: Here, we compare the role of Oct4 and Nanog, two-core pluripotent TFs, in transformed (t-hPSCs), and normal human pluripotent stem cells (hPSCs). Unlike normal SCs, self-renewal and survival of t-hPSCs were found to be independent of Oct4. In contrast, t-hPSCs exhibit hypersensitivity to reduction in Nanog and demonstrate complete loss of self-renewal coupled with apoptosis. Dual and sequential knockdown of Oct4 and Nanog revealed that sensitivity of t-hPSCs to Nanog was Oct4 dependent. CONCLUSIONS/SIGNIFICANCE: Our study indicates a bifurcation for the role of two-core SC and cancer related TFs in self-renewal and survival processes. We suggest that the divergent roles of these TFs establish a paradigm to develop novel therapeutics towards selective destruction of aggressive tumors harboring cancer stem cells (CSCs) with similar molecular signatures.", "link"=>"http://www.mendeley.com/research/pluripotent-transcription-factors-possess-distinct-roles-normal-versus-transformed-human-stem-cells-4", "reader_count"=>3, "reader_count_by_academic_status"=>{"Researcher"=>1, "Other"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>1, "Other"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Materials Science"=>1, "Agricultural and Biological Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/873530"], "description"=>"<p>(A–D) Representative images of colonies generated from GFP<sup>+</sup>SSEA3<sup>+</sup> cells 11 days post-sort from control (A and B) and Oct4 knockdown (C and D) normal hPSCs. Scale bar = 100 µm, n = 3. Note the compact appearance and well-defined border of the typical hPSC colony in A and B. In contrast, the cells within the more differentiated colony in C and D exhibit a higher cytoplasm to nuclear ratio, are less compact, and do not form a well-defined colony border. (E) qPCR of fold changes in Oct4, Nanog, Sox2, c-Myc, Dpp4a, and Tbx3 transcripts in Oct4 knockdown hPSCs relative to hPSC <sup>eGFP</sup> controls. Bar graphs represent mean values ± SEM, n = 3, ***, p<0.001. (F) Clonogenic self-renewal of SSEA3<sup>+</sup> cells isolated from control (39.3±4.3×10<sup>4</sup>) and Oct4 knockdown (14±2.3×10<sup>4</sup>) hPSCs. 1×10<sup>4</sup> GFP<sup>+</sup>SSEA3<sup>+</sup> cells were isolated from hPSCs 2 days after transduction with eGFP control and Oct4 knockdown lentiviral vectors and seeded on ihdFs. GFP<sup>+</sup> colonies were scored 9 days after seeding. Bar graphs represent mean values ± SEM, n = 3. **, p<0.01. (G–I) Frequency of GFP<sup>+</sup>SSEA3<sup>+</sup> (G) GFP+A2B5+ (H) and GFP+AnnexinV+ (I) cells for three passages of culture derived from sorted GFP<sup>+</sup>SSEA3<sup>+</sup> fractions of control and Oct4 knockdown hPSCs. N = 3 for each. Line graphs represent mean values ± SEM. * p<0.05, ** p<0.01. (J–M) Representative images of colonies generated from sorted GFP<sup>+</sup> cells 6 days post-sort from control (J–K) and Oct4 knockdown (L–M) t-hPSCs. Scale bar = 100 µm, n = 5. Arrow denotes the typical appearance of tightly packed undifferentiated colonies. (N) qPCR of fold changes in Oct4, Nanog, Sox2, c-Myc, Dpp4a, and Tbx3 transcripts in Oct4 knockdown t-hPSCs relative to t-hPSC <sup>eGFP</sup> control cells. Bar graphs represent mean values ± SEM, n = 3, **, p<0.01, ***, p<0.001. (O) Clonogencity of GFP<sup>+</sup> cells isolated from control and Oct4 knockdown t-hPSCs. 1×10<sup>4</sup> GFP<sup>+</sup> cells were sorted from t-hPSCs 4 days after transduction with eGFP control and Oct4 knockdown lentiviral vectors and seeded on ihdFs. GFP<sup>+</sup> Colonies were scored 6 days after. Bar graphs represent mean values ± SEM, n = 3. (P–R) Frequency of GFP<sup>+</sup>SSEA3<sup>+</sup> (P) GFP+A2B5+ (Q) and GFP+AnnexinV+ (R) cells for three passages of culture derived from sorted GFP<sup>+</sup> fractions of control and Oct4 knockdown t-hPSCs. P, n = 9. Q, n = 5, R, n = 3. Line graphs represent mean values ± SEM.</p>", "links"=>[], "tags"=>["knockdown", "differentiation"], "article_id"=>543984, "categories"=>["Cancer", "Cell Biology"], "users"=>["Junfeng Ji", "Tamra E. Werbowetski-Ogilvie", "Bonan Zhong", "Seok-Ho Hong", "Mickie Bhatia"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008065.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Oct4_knockdown_does_not_affect_self_renewal_differentiation_and_survival_of_t_hPSCs_/543984", "title"=>"Oct4 knockdown does not affect self-renewal, differentiation and survival of t-hPSCs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-30 01:06:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/873815"], "description"=>"<p>(A–B) Representative images of normal hPSC bulk culture one week after transduction with a lentivector carrying an shRNA sequence targeting Nanog. Scale bar = 100 µm, n = 5. A: Phase contrast. B: GFP. Note the less compact colony morphology and the differentiated interior. Arrow denotes differentiated cells in the hPSC colony centre following Nanog knockdown. (C) qPCR demonstrating fold changes in Oct4, Nanog, Sox2, c-Myc, Dpp4a, and Tbx3 transcripts in GFP<sup>+</sup>SSEA3<sup>+</sup> cells isolated from Nanog knockdown hPSCs relative to the control, respectively. Bar graphs represent mean values ± SEM, n = 3. **, p<0.01, ***, p<0.001. (D) Clonogenic self-renewal of SSEA3<sup>+</sup> cells isolated from control and Nanog knockdown hPSCs. 1×10<sup>4</sup> GFP<sup>+</sup>SSEA3<sup>+</sup> cells were isolated from hPSCs 2 days after transduction with eGFP control and Nanog knockdown lentiviral vectors and seeded on ihdFs. GFP<sup>+</sup> colonies were scored 9 days after seeding. Bar graphs represent mean values ± SEM, n = 3. **, p<0.01. (E–G) Frequency of GFP<sup>+</sup>SSEA3<sup>+</sup> (E) GFP+A2B5+ (F) and GFP+AnnexinV+ (G) cells for three passages of culture derived from sorted GFP<sup>+</sup>SSEA3<sup>+</sup> fractions of control and Nanog knockdown hPSCs. Lines represent mean values ± SEM, n = 3. * p<0.05, ** p<0.01. (H–I) Representative images of t-hPSC bulk culture one week after transduction with a lentivector carrying an shRNA sequence targeting Nanog. Scale bar = 100 µm, n = 5. H: Phase contrast. I: GFP. Arrow denotes t-hPSCs undergoing apoptosis following Nanog downregulation. (J) qPCR demonstrating fold changes in Oct4, Nanog, Sox2, c-Myc, Dpp4a, and Tbx3 transcript in GFP<sup>+</sup> cells isolated from Nanog knockdown t-hPSCs. Bar graphs represent mean values ± SEM, n = 3, *, p<0.05, **, p<0.01, ***, p<0.001. (K) Clonogenic self-renewal of GFP<sup>+</sup> cells isolated from control and Nanog knockdown t-hPSCs. 1×10<sup>4</sup> were sorted from t-hPSCs 4 days after transduction with eGFP control and Nanog knockdown lentiviral vectors and seeded on ihdFs. GFP<sup>+</sup> colonies were scored 6 days after seeding. Bar graphs represent mean values ± SEM, n = 3. **, p<0.01. (L–N) Frequency of GFP<sup>+</sup>SSEA3<sup>+</sup> (L) GFP+A2B5+ (M) and GFP+AnnexinV+ (N) cells for three passages of control and Nanog knockdown t-hPSCs. Lines represent mean values ± SEM, n = 3. * p<0.05.** p<0.01.</p>", "links"=>[], "tags"=>["heightened", "self-renewal", "nanog"], "article_id"=>544273, "categories"=>["Cancer", "Cell Biology"], "users"=>["Junfeng Ji", "Tamra E. Werbowetski-Ogilvie", "Bonan Zhong", "Seok-Ho Hong", "Mickie Bhatia"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008065.g003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_t_hPSCs_exhibit_a_heightened_self_renewal_and_survival_response_following_Nanog_dysregulation_/544273", "title"=>"t-hPSCs exhibit a heightened self-renewal and survival response following Nanog dysregulation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-30 01:11:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/873679"], "description"=>"<p>(A) Summary of teratoma formation from control and Oct4 knockdown t-hPSCs at serial injected cell doses. Cell doses of 7.5×10<sup>3</sup>, 2.4×10<sup>4</sup>, and 6.6×10<sup>4</sup> t-hPSCs and 1.5×10<sup>4</sup>, 3.3×10<sup>4</sup> and 6.6×10<sup>4</sup> Oct4 knockdown t-hPSCs were injected into the testis capsules of NOD/SCID mice. Mice were sacrificed 6 weeks after injection. Teratoma size was measured and plotted relative to injected cell doses. N = 7. (B–G) Representative histology of teratomas formed in NOD/SCID mice testes 6 weeks following injection of control t-hPSCs (B–D, upper panel) or Oct4 knockdown t-hPSCs (E–G, bottom panel). Tissues representing all three embryonic germ layers including ectoderm (neural rosettes, B and E, left panels), mesoderm (cartilage, C and F, middle panels), and endoderm (columnar epithelium, D and G, right panels) are shown. Scale bar = 50 µm.</p>", "links"=>[], "tags"=>["oct4", "t-hpsc", "pluripotency", "tumor-initiating"], "article_id"=>544133, "categories"=>["Cancer", "Cell Biology"], "users"=>["Junfeng Ji", "Tamra E. Werbowetski-Ogilvie", "Bonan Zhong", "Seok-Ho Hong", "Mickie Bhatia"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008065.g002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Downregulation_of_Oct4_has_no_effect_on_t_hPSC_pluripotency_or_tumor_initiating_cell_capacity_/544133", "title"=>"Downregulation of Oct4 has no effect on t-hPSC pluripotency or tumor-initiating cell capacity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-30 01:08:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/873972"], "description"=>"<p>(A) Schematic showing the protocol for dual and sequential knockdown of Oct4 and Nanog in t-hPSCs. (B–I) Representative images of control (B–E) and dual Oct4 and Nanog knockdown (F–I) t-hPSCs 2 weeks after transduction with the shOct4_GFP vector followed by control DsRed and shNanog_DsRed vectors, respectively. Scale bar = 100 µm, n = 3. Images are representative of individual colonies seen throughout the entire culture. Note the significant overlay between Oct4 KD-dsRED (E) and Oct4 KD-Nanog KD (I) demonstrating that Oct4 and Nanog are downregulated in the same cells. (J) Representative FACS results showing the frequencies of Annexin V<sup>+</sup> cells within GFP<sup>+</sup>DsRed<sup>+</sup> fractions of control and dual Oct4 and Nanog knockdown t-hPSCs. n = 3. (K) Frequency of Annexin V<sup>+</sup> cells within GFP<sup>+</sup>DsRed<sup>+</sup> fractions of control and dual Oct4 and Nanog knockdown t-hPSCs. (13±2.1% AnnexinV+ cells in Oct4 KD/dsRED t-hPSC controls vs 15.9±9.2% Annexin V+ cells in Oct4 KD/Nanog KD-dsRED t-hPSCs. Bar graphs represent mean values ± SEM, n = 3, p>0.05. (L) While both Oct4 and Nanog are required to sustain the normal human stem cell pluripotent state, Oct4 is dispensable for transformed human stem cell self-renewal and survival. However, transformed human stem cells are completely dependent on Nanog for both self-renewal and survival revealing a fundamental paradigm shift in the role of core TFs following transformation. This heightened effect of Nanog on transformed cell survival is dependent on Oct4.</p>", "links"=>[], "tags"=>["t-hpscs", "dual", "sequential", "knockdown", "oct4"], "article_id"=>544421, "categories"=>["Cancer", "Cell Biology"], "users"=>["Junfeng Ji", "Tamra E. Werbowetski-Ogilvie", "Bonan Zhong", "Seok-Ho Hong", "Mickie Bhatia"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008065.g004", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Survival_of_t_hPSCs_after_dual_and_sequential_knockdown_of_Oct4_and_Nanog_/544421", "title"=>"Survival of t-hPSCs after dual and sequential knockdown of Oct4 and Nanog.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-30 01:13:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/433589", "https://ndownloader.figshare.com/files/433599", "https://ndownloader.figshare.com/files/433601", "https://ndownloader.figshare.com/files/433603"], "description"=>"<div><h3>Background</h3><p>Cancer and normal stem cells (SCs) share proliferative properties of self-renewal and expression of key transcription factors (TFs). Despite similar TF identities, the functional role of specific TFs responsible for retaining SC state has yet to be examined in cancer.</p><h3>Methodology/Principal Findings</h3><p>Here, we compare the role of <em>Oct4</em> and <em>Nanog</em>, two-core pluripotent TFs, in transformed (t-hPSCs), and normal human pluripotent stem cells (hPSCs). Unlike normal SCs, self-renewal and survival of t-hPSCs were found to be independent of Oct4. In contrast, t-hPSCs exhibit hypersensitivity to reduction in Nanog and demonstrate complete loss of self-renewal coupled with apoptosis. Dual and sequential knockdown of Oct4 and Nanog revealed that sensitivity of t-hPSCs to Nanog was Oct4 dependent.</p><h3>Conclusions/Significance</h3><p>Our study indicates a bifurcation for the role of two-core SC and cancer related TFs in self-renewal and survival processes. We suggest that the divergent roles of these TFs establish a paradigm to develop novel therapeutics towards selective destruction of aggressive tumors harboring cancer stem cells (CSCs) with similar molecular signatures.</p></div>", "links"=>[], "tags"=>["pluripotent", "transcription", "factors", "roles", "transformed", "cells"], "article_id"=>145533, "categories"=>["Cancer", "Cell Biology"], "users"=>["Junfeng Ji", "Tamra E. Werbowetski-Ogilvie", "Bonan Zhong", "Seok-Ho Hong", "Mickie Bhatia"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0008065.s001", "https://dx.doi.org/10.1371/journal.pone.0008065.s002", "https://dx.doi.org/10.1371/journal.pone.0008065.s003", "https://dx.doi.org/10.1371/journal.pone.0008065.s004"], "stats"=>{"downloads"=>3, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Pluripotent_Transcription_Factors_Possess_Distinct_Roles_in_Normal_versus_Transformed_Human_Stem_Cells/145533", "title"=>"Pluripotent Transcription Factors Possess Distinct Roles in Normal versus Transformed Human Stem Cells", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-11-30 01:32:13"}

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